Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy
Yan-ping Xu, … , Jeffrey Aubé, Yue Xiong
Yan-ping Xu, … , Jeffrey Aubé, Yue Xiong
Published October 1, 2019; First published July 16, 2019
Citation Information: J Clin Invest. 2019;129(10):4316-4331. https://doi.org/10.1172/JCI129317.
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Research Article Cell biology Oncology

Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy

Abstract

Loss-of-function mutations in genes encoding TET DNA dioxygenase occur frequently in hematopoietic malignancy, but rarely in solid tumors, which instead commonly have reduced activity. The impact of decreased TET activity in solid tumors is not known. Here we show that TET2 mediates the IFN-γ/JAK/STAT signaling pathway to control chemokine and PD-L1 expression, lymphocyte infiltration, and cancer immunity. IFN-γ stimulated STAT1 to bind TET2 and recruit TET2 to hydroxymethylate chemokine and PD-L1 genes. Reduced TET activity was associated with decreased Th1-type chemokines and tumor-infiltrating lymphocytes and the progression of human colon cancer. Deletion of Tet2 in murine melanoma and colon tumor cells reduced chemokine expression and tumor-infiltrating lymphocytes, enabling tumors to evade antitumor immunity and to resist anti–PD-L1 therapy. Conversely, stimulating TET activity by systematic injection of its cofactor ascorbate/vitamin C increased chemokines and tumor-infiltrating lymphocytes, leading to enhanced antitumor immunity and anti–PD-L1 efficacy and extended lifespan of tumor-bearing mice. These results suggest an IFN-γ/JAK/STAT/TET signaling pathway that mediates tumor response to anti–PD-L1/PD-1 therapy and is frequently disrupted in solid tumors. Our findings also suggest TET activity as a biomarker for predicting the efficacy of and patient response to anti–PD-1/PD-L1 therapy, and stimulation of TET activity as an adjuvant immunotherapy of solid tumors.

Authors

Yan-ping Xu, Lei Lv, Ying Liu, Matthew D. Smith, Wen-Cai Li, Xian-ming Tan, Meng Cheng, Zhijun Li, Michael Bovino, Jeffrey Aubé, Yue Xiong

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Figure 1

Loss of Tet2 confers tumor resistance to immunotherapy.

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Loss of Tet2 confers tumor resistance to immunotherapy. (A) Western blot...
(A) Western blot confirmation of Tet2 KO in B16-OVA melanoma cells is shown. (B) Tet2-KO B16-OVA cells proliferated similarly to wild-type cells in culture. Proliferation curves for Tet2-WT and -KO B16-OVA cells were determined by seeding of the same number of cells and counting every day. Error bars represent cell numbers ± SD for triplicate experiments. (C) Tet2-KO B16-OVA cell–derived tumors grow similarly to wild-type cells in nude mice. A quantity of 2 × 105 WT or Tet2-KO B16-OVA cells were injected s.c. into nude mice, and tumor volume and weight were determined and analyzed. Data represent mean ± SEM for 8 tumors. (D) Kaplan-Meier survival curves for mice injected with WT or Tet2-KO B16-OVA cells and treated with adoptive T cell immunotherapy are shown. A quantity of 2 × 105 WT or Tet2-KO B16-OVA cells were injected s.c. into C57BL/6 mice at day 0 and 5 × 106 OT-I cells injected i.v. at day 15. Kaplan-Meier survival curves for these mice are shown (n = 10 mice for groups without OT-I injection and n = 12 mice for groups with OT-I injection). (E) Kaplan-Meier survival curves for mice injected with WT or Tet2-KO B16-OVA cells and treated with anti–PD-L1 therapy are shown (n = 10 mice for each group). A quantity of 2 × 105 WT or Tet2-KO B16-OVA cells were injected s.c., and anti–PD-L1 antibody was injected i.p., into C57BL/6 mice at the indicated time points. The survival curve of mice injected with only WT or Tet2-KO B16-OVA cells without treatment in D is also shown by the dashed gray or pink line for reference. The P values of D and E are shown in the tables at right, determined using log-rank (Mantel-Cox) test comparing each 2 groups; ***P < 0.001.